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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(2;5)(p23;q35) SQSTM1/ALK Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: November 2011 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0205p23q35ID1584.html DOI: 10.4267/2042/47305 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology one glycin-rich region), a transmembrane domain, and an intracellular region (composed of a tyrosine kinase domain). Membrane receptor tyrosine kinase. Germinal mutations In familial neuroblastoma. Somatic mutations Fusion proteins in anaplastic large cell lymphoma, some diffuse large B-cell lymphomas, inflammatory myofibroblastic tumours, and some non-small cell lung cancers. Somatic mutations in sporadic neuroblastoma (review in Allouche, 2010). Identity Note Not to be confused with the t(2;5)(p23;q35) with NPM1-ALK involvement. Clinics and pathology Disease ALK-positive large B-cell lymphoma (ALK+ LBCL) Phenotype/cell stem origin SQSTM1 One case to date, a 67-year-old male patient (Takeuchi et al., 2011). Location 5q35.3 Protein SQSTM1 (sequestosome1), also called p62, is a scaffolding protein with several interaction domains; it is composed of an OPR domain (octicosapeptide repeat (PB1 dimerization domain)), a Zn finger, a LIM protein-binding region, a TRAF6-binding motif, a PEST sequence (proline, glutamic acid, serine, and threonine rich), a LIR motif (LC3 interaction region, SGGDDDWTHLSS), a second PEST sequence, a KIR (keap1 interacting region), and an UBA (ubiquitinassociated) domain. Interacts with Caspase-8 and the apoptosis, machinery, MAPK kinases such as MAP2K5 (15q23), LCK (1p34), NBR1 (17q21), PRKCI (3q26), PAWR (12q21), RIPK1 (6p25), TRAF6 (11p12) and NTRK1 (1q23) and the NF-kappaB pathway, KEAP1 (19p13), GABARAPL1 (12p13), MAP1LC3A/LC3 (20q11), and ubiquitin. Mediates the interaction between TRAF6 and CYLD (16q12). Implicated in the activation of the transcription factor NF-kappaB. Cytology Anti-ALK immunohistochemistry showed a diffuse cytoplasmic staining pattern, in contrast with the nuclear and cytoplasmic pattern usually sen in the NPM1-ALK fusion gene/protein. Prognosis Complete remission was obtained, but the patient relapsed four months later. Genes involved and proteins ALK Location 2p23 Protein ALK is composed of an extracellular region (containing two MAM (meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu) and one LDLa (low-density lipoprotein receptor) domains, and Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4) 293 t(2;5)(p23;q35) SQSTM1/ALK Huret JL Lamark T, Kirkin V, Dikic I, Johansen T. NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle. 2009 Jul 1;8(13):1986-90 Involved in the autophagy-lysosome pathway. Plays a role in the formation of cytoplasmic proteinaceous inclusions in various pathologic situations where autophagy is inactivated (Geetha and Wooten, 2002; Lamark et al., 2009; Moscat and Diaz-Meco, 2009; Moscat et al., 2009; Ichimura and Komatsu, 2010; Komatsu and Ichimura, 2010; Moscat and Diaz-Meco, 2011). Germinal mutations Mutated in Paget's disease of bone. Moscat J, Diaz-Meco MT. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell. 2009 Jun 12;137(6):1001-4 Moscat J, Diaz-Meco MT, Wooten MW. Of the atypical PKCs, Par-4 and p62: recent understandings of the biology and pathology of a PB1-dominated complex. Cell Death Differ. 2009 Nov;16(11):1426-37 Allouche M.. ALK (anaplastic lymphoma receptor tyrosine kinase) Atlas Genet Cytogenet Oncol Haematol. February 2010. URL: http://AtlasGeneticsOncology.org/Genes/ALK.html Result of the chromosomal anomaly Ichimura Y, Komatsu M.. Selective degradation of p62 by autophagy. Semin Immunopathol. 2010 Dec;32(4):431-6. Epub 2010 Sep 3. (REVIEW) Komatsu M, Ichimura Y.. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett. 2010 Apr 2;584(7):1374-8. Epub 2010 Feb 12. (REVIEW) Hybrid gene Description Exon 5 of SQSTM1 fused to the ALK exon 20. Fusion protein Moscat J, Diaz-Meco MT.. Feedback on fat: p62-mTORC1autophagy connections. Cell. 2011 Nov 11;147(4):724-7. (REVIEW) Description Fuses the PB1 dimerization domain of SQSTM1 to the tyrosine kinase domain of ALK, resulting in a constitutive activation of the ALK kinase domain. Takeuchi K, Soda M, Togashi Y, Ota Y, Sekiguchi Y, Hatano S, Asaka R, Noguchi M, Mano H.. Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma. Haematologica. 2011 Mar;96(3):464-7. Epub 2010 Dec 6. This article should be referenced as such: References Huret JL. t(2;5)(p23;q35) SQSTM1/ALK. Atlas Cytogenet Oncol Haematol. 2012; 16(4):293-294. Geetha T, Wooten MW. Structure and functional properties of the ubiquitin binding protein p62. FEBS Lett. 2002 Feb 13;512(1-3):19-24 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4) 294 Genet